Myelin Lipids Inhibit Axon Regeneration Following Spinal Cord Injury: a Novel Perspective for Therapy

Abstract

Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rho-dependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2-hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury.

Role of cholesterol and sphingolipids in brain development and neurological diseases

“…Peripheral nerve injury (PNI) can have a potentially devastating impact on a patient’s quality of life, resulting in severe disability with substantial social and personal cost [40]. The requirement of cholesterol is increased in the case of nerve regeneration as it is an important modulator of axon regeneration following nerve injury [41]. Cholesterol plays a crucial role in the regeneration of nerve after injuries both in CNS and PNS.…”

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

“…By lowering cholesterol synthesis, molecular and pharmacological strategies have proven effective in promoting survival and CNS regeneration of retinal ganglion cells after optic nerve injury [ 73 ]. Work done in mice deficient for CNS myelin and myelin basic protein (also known as shiverer mice [ 74 ]) has demonstrated the inhibitory action of CNS myelin lipids, in particular cholesterol and sphingomyelin, to axon regeneration after SCI [ 75 ]. Shiverer mice, but also mice administered 2-hydroxypropyl-β-cyclodextrin to scavenge lipids at the injury site, showed increased regeneration of dorsal column sensory axons after SCI [ 75 ].…”

Inhibitors of CNS regeneration, their physiological role and participation in pathogenesis of diseases

“…Аксональные контакты и восстановление в ЦНС блокируют остатки миелина, нейровоспаление и клеточная гибель в месте повреждения. Хондроитинсульфатные протеогликаны экстрацеллюлярного матрикса образуют глиальный рубец и периневральный барьер для аксонального роста и спрутинга [53][54][55]. Соответственно спонтанное восстановление после спинальной травмы, небольшие степени которого все же наблюдаются в клинике и эксперименте, зависит от присутствия миелинассоциированных протеинов-ингибиторов роста, воспалительного компонента в поврежденной нервной ткани, гиперактивации сигнального Rho-пути [56].…”

“…В экспериментальных работах показана значимая роль в данной патологии миелинассоциированного протеина Nogo-A [56], липидов миелина [54], хондроитинсульфатных протеогликанов [53]. На культурах клеток в среде, лишенной этих молекул, аксонотомированные нейроны демонстрировали элонгацию аксонального конуса, животные нокаутных по генам миелинассоциированных протеинов линий лучше восстанавливались после экспериментальных спинальных повреждений.…”